A Phase 3, Randomized, Active-Controlled, Double-Blind Clinical Study to Evaluate the Antiretroviral Activity, Safety, and Tolerability of Doravirine/Islatravir (DOR/ISL 100 mg/0.25 mg) Once-Daily in HIV-1 Infected Treatment-Naïve Participants

The primary objective of this Phase 3, randomized, active-controlled, double-blind clinical study is to evaluate the **antiretroviral activity** of Doravirine/Islatravir (DOR/ISL) compared to Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF). This is assessed by the percentage of participants with **HIV-1 RNA** levels below 50 copies/mL at Week 48. Additionally, the study aims to assess the safety and tolerability of DOR/ISL compared with BIC/FTC/TAF through a review of accumulated safety data up to Week 48. These objectives are clinically relevant as they provide insights into the efficacy and safety of a new antiretroviral regimen for treatment-naïve individuals with HIV-1 infection.

Secondary objectives include: - Evaluating the antiretroviral activity of DOR/ISL compared with BIC/FTC/TAF, as assessed by the percentage of participants with HIV-1 RNA <50 copies/mL at Week 96 and Week 144, and <200 copies/mL at Week 48, Week 96, and Week 144. - Assessing the immunologic effect of DOR/ISL compared with BIC/FTC/TAF, as measured by the mean change from baseline in **CD4+ T-cell** count at Week 48, Week 96, and Week 144. - Evaluating the development of viral drug resistance in participants receiving DOR/ISL and those receiving BIC/FTC/TAF. - Assessing the effect of DOR/ISL compared with BIC/FTC/TAF on weight, as measured by the mean change from baseline to Week 48, Week 96, and Week 144. - Evaluating the safety and tolerability of DOR/ISL compared with BIC/FTC/TAF through a review of accumulated safety data up to Week 144.

The clinical trial involves a total of **560 participants** diagnosed with **HIV-1 Infection**. The study population includes individuals aged 18 years and older, encompassing both male and female participants. Participants are required to be **naïve to antiretroviral therapy (ART)**, meaning they have not received any prior therapy with antiretroviral agents following their diagnosis. The trial does not specifically target a vulnerable population. Participants must have a plasma HIV-1 RNA level of at least 500 copies/mL at screening. Female participants of childbearing potential must not be pregnant or breastfeeding and are required to use an acceptable contraceptive method or abstain from heterosexual intercourse for the duration of the study. The selection criteria ensure a focus on individuals who are new to ART, providing a clear baseline for evaluating the antiretroviral activity and safety of the treatments under investigation.

The clinical trial is a **randomized**, **double-blind**, and **active-controlled** study designed to evaluate the antiretroviral activity, safety, and tolerability of **doravirine**/**islatravir** (DOR/ISL) compared to **bictegravir**/**emtricitabine**/**tenofovir alafenamide** (BIC/FTC/TAF) in treatment-naïve participants with **HIV-1 infection**. The trial is set to commence recruitment on March 1, 2024, and is estimated to conclude on August 6, 2029. The study will involve a series of visits, beginning with a screening visit to confirm eligibility based on criteria such as being HIV-1 positive with plasma HIV-1 RNA ≥500 copies/mL and being naïve to antiretroviral therapy. Participants will be randomly assigned to receive either the DOR/ISL or BIC/FTC/TAF regimen, with the primary objective of assessing the percentage of participants achieving HIV-1 RNA <50 copies/mL at Week 48.

Study visits will be scheduled at regular intervals to monitor the participants' health, adherence to the medication regimen, and any adverse events. The primary endpoint will be evaluated at Week 48, with secondary endpoints assessed at Weeks 96 and 144, including changes in CD4+ T-cell counts and body weight, as well as the incidence of viral drug resistance. The expected duration of participant involvement is up to 144 weeks, with conditions for early termination including the occurrence of significant adverse events or withdrawal of consent. The trial will ensure that all participants are blinded to the treatment allocation to maintain the integrity of the study outcomes.

The clinical trial involves the administration of **MK-8591A**, a combination of **doravirine** and **islatravir**, formulated as a film-coated tablet. This investigational medication is administered orally once daily. The maximum daily dose is 100.25 mg, with a total treatment period of up to 96 weeks. The active substances, doravirine and islatravir, are of chemical origin and are provided by Merck & Co. Inc. The trial aims to evaluate the antiretroviral activity, safety, and tolerability of this combination in treatment-naïve participants infected with HIV-1.

**Biktarvy** is used as a comparator treatment in this study. It is a film-coated tablet containing a combination of **emtricitabine**, **tenofovir alafenamide**, and **bictegravir**. The medication is administered orally once daily, with a maximum daily dose of 275 mg. The treatment period extends up to 96 weeks. Biktarvy is provided by Gilead Sciences Ireland UC and is repackaged into HDPE bottles with induction seals and child-resistant closures. This comparator is used to assess the efficacy and safety of the investigational treatment against a standard-of-care therapy.

Two placebo treatments are included in the study: a placebo to bictegravir/emtricitabine/tenofovir alafenamide and a placebo to doravirine/islatravir. These placebos are used to maintain the double-blind nature of the trial. The pharmaceutical form, active substances, and administration routes for these placebos are not specified. The use of placebos helps to ensure that the observed effects in the trial are attributable to the active treatments being tested.

The efficacy of the investigational treatment in this clinical trial will be assessed primarily by evaluating the **antiretroviral activity** of Doravirine/Islatravir (DOR/ISL) compared to Biktarvy (BIC/FTC/TAF). The primary endpoint for efficacy is the percentage of participants with HIV-1 RNA levels below 50 copies/mL at Week 48. Secondary endpoints include the percentage of participants with HIV-1 RNA levels below 50 copies/mL at Week 96 and Week 144, as well as the percentage of participants with HIV-1 RNA levels below 200 copies/mL at Weeks 48, 96, and 144. Additional secondary endpoints involve changes from baseline in CD4+ T-cell counts and body weight at Weeks 48, 96, and 144, and the incidence of viral drug resistance.

The efficacy parameters will be measured at specified timepoints throughout the trial, including Weeks 48, 96, and 144. The collection and analysis of these parameters will be conducted using standardized laboratory tests to quantify HIV-1 RNA levels and assess CD4+ T-cell counts. The trial will also monitor the safety and tolerability of the treatment by reviewing accumulated safety data, including the percentage of participants experiencing adverse events (AEs) and those discontinuing treatment due to AEs through Week 48 and Week 96.